1. Field of the Invention (Technical Field)
The present invention relates to cyclic hexapeptides that are highly-specific antagonists for the melanocortin-4 receptor (MC4-R), and which may be used in the treatment of a variety of body weight disorders including cachexia, sarcopenia and wasting syndrome or disease, and for treatment of inflammation and immune disorders.
2. Description of Related Art
Note that the following discussion refers to a number of publications by author(s) and year of publication, and that due to recent publication dates certain publications are not to be considered as prior art vis-a-vis the present invention. Discussion of such publications herein is given for more complete background and is not to be construed as an admission that such publications are prior art for patentability determination purposes.
Melanocortin Receptors. A family of melanocortin receptor types and subtypes have been identified, including melanocortin-1 receptors (MC1-R) expressed on normal human melanocytes and melanoma cells, melanocortin-2 receptors (MC2-R) for ACTH (adrenocorticotropin) expressed in cells of the adrenal gland, melanocortin-3 and melanocortin-4 receptors (MC3-R and MC4-R) expressed primarily in cells in the hypothalamus, mid-brain and brainstem, and melanocortin-5 receptors (MC5-R), expressed in a wide distribution of peripheral tissues.
Significant work has been done in determining the structure of melanocortin receptors, including both the nucleic acid sequences encoding for the receptors and the amino acid sequences constituting the receptors. MC4-R is a G protein-coupled, 7-transmembrane receptor that is believed to be expressed primarily in the brain. Inactivation of this receptor by gene targeting has been reported to result in mice with the maturity-onset obesity syndrome that is associated with hyperphagia, hyperinsulinemia, and hyperglycemia (Huszar D., Lynch C. A., Fairchild-Huntress V., et al. Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell 88:131-141 (1997)). MC4-R is a molecular target for therapeutic intervention in energy homeostasis.
In general, compounds specific for MC4-R, and secondarily compounds specific for MC3-R or MC5-R, are believed to be useful in regulation of mammalian energy homeostasis, including use as agents for attenuating food intake and body weight gain. MC4-R antagonists are believed to be useful for weight gain aid, such as for use in treatment of cachexia, sarcopenia, wasting syndrome or disease, and anorexia. MC4-R agonists, by contrast, are believed to be useful for decreasing food intake and body weight gain, such as for treatment of obesity. Compounds that are antagonists specific for MC3-R and MC4-R are additionally believed to be useful in regulating blood pressure, heart rate and other neurophysiologic parameters.
Cachexia and Other Wasting Diseases. Body weight disorders include one or more “wasting” disorders (e.g., wasting syndrome, cachexia, sarcopenia) which cause undesirable and unhealthy loss of weight or loss of body cell mass. In the elderly as well as in cancer and AIDS patients, wasting diseases can result in undesired loss of body weight, including both the fat and the fat-free compartments. Wasting diseases can be the result of inadequate intake of food and/or metabolic changes related to illness and/or the aging process. Cancer patients and AIDS patients, as well as patients following extensive surgery or having chronic infections, immunologic diseases, hyperthyroidism, Crohn's disease, psychogenic disease, chronic heart failure or other severe trauma, frequently suffer from wasting disease. Wasting disease is sometimes also referred to as cachexia, and is generally recognized as a metabolic and, sometimes, an eating disorder. Cachexia may additionally be characterized by hypermetabolism and hypercatabolism. Although cachexia and wasting disease are frequently used interchangeably to refer to wasting conditions, there is at least one body of research which differentiates cachexia from wasting syndrome as a loss of fat-free mass, and particularly, body cell mass (Roubenoff R. The pathophysiology of wasting in the elderly. J. Nutr. 129(1S Suppl.):256S-259S (1999)). Sarcopenia, yet another such disorder which can affect the aging individual, is typically characterized by loss of muscle mass. End stage wasting disease as described above can develop in individuals suffering from either cachexia or sarcopenia.
Melanocortin Antagonist Peptides. Antagonist peptides are based on modifications of the alpha-melanocyte stimulating hormone (α-MSH) core sequence, His-Phe-Arg-Trp (SEQ ID NO:1), and generally include a D-amino acid at the Phe position, most commonly a D-amino acid with a 1- or 2-naphthyl ring or phenyl ring, which may optionally be a substituted ring. Thus U.S. Pat. No. 5,731,408 discloses cyclic lactam heptapeptides that are non-specific antagonists for melanocortin receptors MC3-R and MC4-R, and contain either D-Phe(4-I) or D-Nal 2 in place of the Phe residue. Of particular note is a peptide commonly called SHU9119 (Ac-Nle-cyclo(-Asp-His-D-Nal 2-Arg-Trp-Lys)-NH2) disclosed in U.S. Pat. No. 5,731,408. SHU9119 has been extensively used in research as a reference non-specific melanocortin antagonist. Related cyclic lactam heptapeptides are disclosed in U.S. Pat. No. 6,054,556, which are antagonists for melanocortin receptors MC1-R, MC3-R, MC4-R and MC5-R. These peptides all contain an optionally substituted D-Phe or D-Nal 2 in place of the Phe residue.
Other patents teach the use of melanocortin antagonists for treatment of cachexia and other weight-related disorders. See, for example, U.S. Pat. Nos. 6,716,810; 6,699,873; 6,693,165; 6,613,874; 6,476,187; 6,284,729; 6,100,048; and 5,908,609. However, none of these disclose the hexapeptides of the present invention. U.S. Pat. No. 6,693,165 discloses cyclic heptapeptides and hexapeptides that are asserted to be selective MC4-R antagonists. These peptides all include a D-amino acid containing an optionally substituted 1- or 2-naphthyl, 3-benzothienyl or phenyl in place of the Phe residue in the His-Phe-Arg-Trp (SEQ ID NO:1) core sequence. However, the peptides disclosed in U.S. Pat. No. 6,693,165 optionally omit the His in the His-Phe-Arg-Trp (SEQ ID NO:1) sequence, and when the His position is present, it is limited to Lys or His.
Published U.S. Application 2003/0113263, “Methods and Reagents for Using Mammalian Melanocortin Receptor Antagonists to Treat Cachexia”, discloses a method for characterizing a compound useful for treating an animal with cachexia, including use of an MC4-R antagonist to treat an animal with cachexia, and specifically disclosing SHU9119. Published U.S. Application 2003/0105024, “Methods and Reagents for Discovering and Using Mammalian Melanocortin Receptor Agonists and Antagonists to Modulate Feeding Behavior in Animals”, discloses SHU9119 as a MC receptor antagonist used experimentally to stimulate feeding behavior. U.S. Pat. No. 6,476,187, “Methods and Reagents for Discovering and Using Mammalian Melanocortin Receptor Agonists and Antagonists to Modulate Feeding Behavior in Animals”, similarly discloses SHU9119 as a MC receptor antagonist used experimentally to stimulate feeding behavior. Published U.S. Application 2003/0032791, “Novel Melanocortin-4 Receptor Sequences and Screening Assays to Identify Compounds Useful in Regulating Animal Appetite and Metabolic Rate”, discloses the experimental use of SHU9119 in various assays. Published U.S. Application 2002/0016291, “Cyclic Peptides as Potent and Selective Melanocortin-4 Receptor Antagonists”, discloses SHU9119 as an antagonist at the MC3 and MC4 receptors. In 1977, it was disclosed that SHU9119 enhanced feeding behavior. Fan W., Boston B. A., Kesterson R. A., Hruby V. J., Cone R. D. Role of melanocortinergic neurons in feeding and the agouti obesity syndrome. Nature 385:165-168 (1997); see also Rossi M., Kim M. S., Morgan D. G., et al. A C-terminal fragment of Agouti-related protein increases feeding and antagonizes the effect of alpha-melanocyte stimulating hormone in vivo. Endocrinology 139:4428-31 (1998); Wisse B. E., Frayo R. S., Schwartz M. W., Cummings D. E. Reversal of cancer anorexia by blockade of central melanocortin receptors in rats. Endocrinology 142:3292-3301 (2001); Marks D. L., Ling N., Cone R. D. Role of the central melanocortin system in cachexia. Cancer Research 61:1432-1438 (2001).
There remains a significant need for ligands with high specificity for discrete melanocortin receptors, and specifically MC4-R, as well as ligands that are antagonists, or optionally inverse agonists, of MC4-R. In order to reduce unintended pharmacological responses, it is desirable that the ligand be highly specific for the target MC receptor, such as MC4-R. Thus it is desirable that the binding affinity of a ligand for MC4-R be higher, such as at least about ten times higher, for MC4-R than for other MC receptors. High affinity and highly specific peptide ligands of MC4-R can be used to exploit varied physiological responses associated with the melanocortin receptors, particularly peptide ligands that are antagonists or inverse agonists. For example, antagonists of MC4-R can be used to treat eating disorders, wasting diseases and cachexia. In addition, melanocortin receptors have an effect on the activity of various cytokines, and high affinity peptide ligands of melanocortin receptors can be used to regulate cytokine activity. Thus such peptide ligands may further be used for treatment of inflammation and other immune disorders.